The results of renal transplantation are good in the short and medium term. However, in the long term, kidneys are consistently lost as a consequence of chronic allograft (transplant) nephropathy. This is largely a consequence of two ongoing phenomena:—(i) chronic rejection; and (ii) calcineurin inhibitor nephrotoxicity. Both of these phenomena interact with a pre-existing determinant of outcome, i.e. chronic damage to the renal parenchyma established prior to and early post transplantation. Furthermore, the requirement for long term immunosuppression in transplant recipients has adverse consequences, such as increased susceptibility to infection and to malignancy.
The benefits of transplantation as treatment for patients suffering from ESRF are manifest both in quality of life and enhanced survival. However, a long wait to be transplanted can be frustrating for the individual and materially affect long-term outcome. A variety of factors determine the waiting time, but particularly important is the presence in the transplant recipient of antibodies that exhibit immunospecificity against polymorphic molecules known as human leukocyte antigens (HLA), present on potential donor organs. Anti-HLA antibodies produced by the transplant recipient can cause a very rapid onset or ‘hyperacute’ rejection of the transplant organ, and their presence must therefore be determined prior to transplantation. The potential recipient is then excluded from receiving a transplant bearing relevant HLA, and the patient must wait for an organ bearing HLA antigens to which antibodies are not produced. Anti-HLA antibodies may be stimulated by pregnancy, blood transfusion and transplantation. The use of erythropoetin has reduced transfusion, and enhanced HLA matching through organ sharing has reduced the stimulation of antibody synthesis by transplantation.
Nevertheless, the production of anti-HLA antibodies, i.e. “HLA sensitisation”, remains a significant problem for transplantation. This is particularly evident in patients who have long-standing ESRF, often from a young age, who have heavy cumulative exposure to allogeneic (i.e foreign HLA). The formation of affinity-matured class switched anti-HLA antibodies by B lymphocytes requires the presence of T cell help. The presence of T cell help for antibody production implies the engagement of HLA by T cell receptors through the indirect pathway. CD4+ T lymphocytes can recognise allogeneic HLA through conventional mechanisms of uptake by autologous antigen presenting cells, processing to peptide and presentation in the context of self-MHC class II. This is called the indirect pathway of allorecognition. As well as its role in antibody formation, T cells are also thought to play a particularly important role in chronic rejection. The direct pathway of allorecognition is the cross-reaction of T cell receptor specific for self-MHC and nominal exogenous peptide on allogeneic MHC (with associated peptide). This is thought to be particularly important in acute rejection. The inventor of the present invention therefore considered that treatment to minimise, prevent or completely abolish the indirect pathway of allorecognition could be of considerable value both prior to and after receiving a transplant in order to reduce the likelihood of rejection and the synthesis of anti-HLA antibodies.
A long-term goal of immunological research in transplantation has been to develop antigen specific modulation of the immune response that would render non-specific immunosuppression unnecessary. Although a complete abrogation of the requirement for immunosuppression may be unrealistic, the inventor realised that any gain in specificity would be welcome.
Non-antigen specific immunosuppression seems to be of limited value in modulating chronic rejection and anti-HLA antibody synthesis. However, while the inventor does not wish to be bound by any hypothesis, they believe that antigen specific reduction or inhibition of indirect presentation could diminish chronic rejection and HLA antibody synthesis. By analogy with evidence in the field of allergy, the inventor speculates that treatments based on fragments of antigen, i.e. peptides, could prove beneficial.